Regulatory evolution in mammalian tissues - Associate Faculty group

Duncan Odom's Associate Faculty group compares how transcription and transcriptional regulation vary during evolution,
and the implications this regulatory plasticity has for diseases such as cancer.

We compare how transcription and transcriptional regulation vary during evolution, and the implications this regulatory
plasticity has for diseases such as cancer. We use numerous new high throughput methods combined with analysis of
multiple mammals and vertebrates to reveal fundamental biological insights into tissue-specification and genome
evolution.

Background

The wide variety in forms and functions among animals we see today is profoundly linked with diseases such as cancer
by the simple fact that they originate from a common source: differences in DNA.

Enormous efforts are being put forth to identify the mutations associated with cancers, but one of the most
formidable challenges today is understanding what these mutations do (or, more often, do not do). There is still a
very poor understanding of which changes in the genome are harmless, and which have an effect of some kind, either
good or bad. We analyze how very divergent genomes from different species can create the same, highly conserved cell
type, liver, and what lessons this conservation holds for understanding the biology of the genome.

Research

Many different kinds of proteins interact with the mammalian genome to direct transcription of specific cell types.
These protein-DNA interactions range from very precise, yet widespread binding of tissue-specific transcription
factors, to the anchorage-like binding of insulator proteins such as CTCF and NRSF, to the basic transcriptional
machinery of the polymerases.

To gain insight into how transcription, evolution, and the rapidly evolving genome interact, the Odom laboratory
(along with our collaborators) have used comparisons of all these layers of transcriptional regulation both:

among different cell types within one species

among the same cell type from many species

For instance, we have discovered that mammalian transcription factors rarely, if ever, show high conservation in
transcription factor binding, as was previously expected. In contrast, insulators are much more frequently conserved,
but are subject to lineage-specific, large-scale remodelling based on activation of repeat elements in the genome. At
the level of the basal machinery, by investigating how RNA polymerase III regulates tRNAs in multuple mammals, we
have discovered that the polymerases responsible for gene expression may be under constraint at the level of their
transcripts, the mechanism for which we are actively investigating.

Our ongoing work at the Sanger Institute will produce a cross-sectional view of the liver epigenome for a wide
variety of vertebrates. In addition, we have begun an integrated cancer systems biology project that combines the
high-throughput experimental expertise at the Wellcome Trust Sanger Institute with the cancer biology approaches from
Cancer Research UK's Cambridge Research Institute.

Collaborations

In addition to many collaborators at Sanger and The Cambridge Research Institute (CRI), we also work closely with a
number of sister groups, including those of: